A Phase I and Pharmacologic Study of Pyrazoloacridine and Cisplatin in Patients with Advanced Cancer
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Pyrazoloacridine (PZA, NSC366140, PD115934) is an acridine derivative currently undergoing clinical evaluation. In preclinical testing, PZA has shown selectivity for solid tumor cell lines, activity in hypoxic, noncycling, and multidrug-resistant cell lines, and synergy with cisplatin in a variety of lung cancer cell lines. In early phase I clinical studies PZA has shown modest activity in ovarian, cervical, and colon cancer. The purpose of the present study was threefold: to determine the maximally tolerated doses of the combination of PZA (3-h infusion) and cisplatin administered with and without Filgrastim (G-CSF) (Amgen, Thousand Oaks, CA) every 3 weeks in untreated or minimally pretreated patients, to describe and quantify the clinical toxicities of combination chemotherapy with PZA and cisplatin, and to evaluate the effects of drug sequencing on the toxicity profile and pharmacologic behavior of PZA. The starting doses in this dose-escalation trial were PZA 400 mg/m2 as a 3-h intravenous infusion and cisplatin 50 mg/m2 as a 1 mg/min intravenous infusion. The sequence of drugs was alternated with each successive course in each patient treated. Twenty-one patients with refractory solid tumors received 43 courses of therapy through four dose levels. Neutropenia was dose-limiting and defined the maximum tolerated dose of PZA 400 mg/m2 and cisplatin 50 mg/m2 without G-CSF support. With G-CSF support, nausea and vomiting were dose-limiting. The maximum tolerated and recommended doses for further study of this combination are PZA 600 mg/m2 over 3 h and cisplatin 50 mg/m2 followed by G-CSF support. Pharmacokinetic analysis showed that sequence does not impact on the pharmacokinetics of PZA when given in combination with cisplatin.
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- 1.Capps D, Ross-Kesten S, Shillis J et al.: 2–aminoalkyl-5–nitropyrazolo-[3,4,5–kl]acridines, a new class of anticancer agents (Abstract). Proc AACR 27: 277, 1986Google Scholar
- 2.Sebolt JS, Scavone SV, Pinter CD, Hamelehle KL, Von Hoff DD, Jackson RC: Pyrazoloacridines, a new class of anticancer agents with selectivity against solid tumors in vitro. Cancer Res 47: 4299–4304, 1987Google Scholar
- 3.Sebolt JS, Havlick M, Hamelehle K, Nelson J, Leopold W, Jackson R: Activity of the pyrazoloacridines against multidrug-resistant tumor cells. Cancer Chemother Pharmacol 24: 219–224, 1989Google Scholar
- 4.Jackson RC, Sebolt JS, Shillis JL, Leopold WR: The pyrazoloacridines: approaches to the development of a carcinom-aselective cytotoxic agent. Cancer Invest 8(1): 39–47, 1990Google Scholar
- 5.Adjei AA, Charron M, Rowinsky EK, Svingen PA, Miller J, Reid JM, Sebolt-Leopold J, Ames MM, Kaufmann SH: Effect of pyrazoloacridine (NSC 366140) on DNA topoisomerases I and II. Clin Cancer Res 4: 683–691, 1998Google Scholar
- 6.Clinical Brochure: Pyrazoloacridine. NSC 366140. Bethesda, MD, Division of Cancer Treatment, NCI, December 1990Google Scholar
- 7.LoRusso P, Foster BJ, Poplin E, McCormick J, Kraut M, Flaherty L, Heilbrun LK, Valdivieso M, Baker L: Phase I clinical trial of pyrazolozcridine NSC366140 (PD 115934). Clin Cancer Res 1(12): 1487–1493, 1995Google Scholar
- 8.Rowinsky EK, Noe DA, Grochow LB, Sartorius SE, Boling MK, Chen T-L, Lubejko B, Kaufmann SH, Donehower RC: Phase I and pharmacologic studies of pyrazoloacridine, a novel DNA intercalating agent, on single-dosing and multiple dosing schedules. J Clin Oncol 13: 1975–1984, 1995Google Scholar
- 9.Adjei AA, Budihardjo II, Rowinsky EK, Kottke TJ, Svingen PA, Buckwalter CA, Grochow LB, Donehower RC, Kaufmann SH: Cytotoxic synergy between pyrazoloacridine (NSC 366140) and cisplatin in vitro: inhibition of platinum-DNA adduct removal. Clin Cancer Res 3: 761–770, 1997Google Scholar
- 10.Rowinsky EK, Gilbert MR, McGuire WP, Noe DA, Grochow LB, Forastiere AA, Ettinger DS, Lubejko BG, Clark B, Sartorius SE: Sequences of taxol and cisplatin: a phase I and pharmacologic study. J Clin Oncol 9(9): 1692–1703, 1991Google Scholar
- 11.Rowinsky EK, Kaufmann SH, Baker SD, Grochow LB, Chen TL, Peereboom D, Bowling MK, Sartorius SE, Ettinger DS, Forastiere AA, Donehower RC: Sequences of topotecan and cisplatin: phase I, pharmacologic, and in vitro studies to examine sequence dependence. J Clin Oncol 14(12): 3074–3084, 1996Google Scholar
- 12.Zalupski MM, Phillip PA, LoRusso P, Shields AF: Phase II study of pyrazoloacridine in patients with advanced colorectal carcinoma. Cancer Chemother Pharmacol 40(3): 225–227, 1997Google Scholar